A Low-Temperature Internal Nucleophilic Aromatic Substitution Reaction on a β-O-4 Lignin Model Dimer

Full text of DOI:10.1021/jo970936z

J . Org. Chem. 1997, 62, 7885-7887
7885
A Low -Tem p er a tu r e In ter n a l Nu cleop h ilic
Ar om a tic Su bstitu tion Rea ction on a â-O-4
Lign in Mod el Dim er †
a scission of the R-C-O bond, one being vanillin, 151/
152 mass, and the other the A ring ion with two side-
chain carbons, which has a mass of 180.
Compounds 1 and 4 were separately reacted with 0.5
M NaOH in dioxane at rt to determine if they were in
equilibrium. Samples were removed at 2, 20, 60, and
Dexter L. Criss, Leonard L. Ingram, J r., and
Tor P. Schultz
1
1
020 min and analyzed by HPLC. After 1020 min, both
and 4 formed mixtures containing approximately equal
Mississippi Forest Products Utilization Laboratory,
Mississippi State University, Mississippi State,
Mississippi 39762
amounts of 1 and 4. This result suggests that the
rearrangement is an equilibrium. Compound 1 appeared
to rearrange slightly faster than 4, since after 60 min 1
showed 28% rearrangement while 4 showed only 20%
rearrangement. No rearrangement product was observed
for either 1 or 4 under acidic conditions.
Thomas H. Fisher* and Debbie B. Saebo
Department of Chemistry, Mississippi State University,
Mississippi State, Mississippi 39762
Received May 28, 1997
Intramolecular nucleophilic aromatic substitution re-
4
actions, including vicarious nucleophilic aromatic sub-
stitution5 of hydrogen, are known but not common. A
stable σ-complexed spiro-Meisenheimer complex with a
diazonium substituent was recently reported.6 Only one
literature example was found of a similar lignin-related
rearrangement. In a study of nitrated kraft lignin,
Lindeberg and Walding7 prepared two lignin models
The major interunit bond in lignin is a â-O-4 link (see
1
in Scheme 1), an ether linkage joining the â-carbon of
the side chain of one phenylpropane lignin unit with the
phenolic oxygen of a second lignin unit.1 The hydrolysis
of this type of nonphenolic lignin ether linkage is believed
to be the rate-limiting step in the bulk-phase alkaline
hydrolysis of wood chips to pulp. We have conducted
structure-reactivity studies on oxidative-cleavage reac-
similar to 1: one model compound (5) contained 2-OMe,4-
NO
2
groups in the B ring and the other (6) contained
substituents on the B ring. â-Aryl ether 5
2
3
tions and alkaline hydrolysis reactions of various â-O-4
lignin models. During the latter studies we observed that
lignin model compound 1 underwent an unusual base-
catalyzed, room-temperature rearrangement reaction to
2
-OMe,5-NO
2
was found to rearrange to an R-aryl ether, while 6 did
not rearrange but instead activated the replacement of
the 2-OMe group with a OH on the B ring. A Meisen-
4
(containing an R-O-4 linkage). This rearrangement can
7
heimer complex was suggested to be an intermediate in
be classified as either a 1,4 oxygen-to-oxygen aryl migra-
tion or an internal nucleophilic aromatic substitution
reaction. We report here mechanistic studies on this
rearrangement.
the rearrrangement, although no mechanistic evidence
was presented. Alternatively, the rearrangement could
occur through a nucleophilic, neighboring-group displace-
ment to give an epoxide, which can open to either an R-
or â-aryl ether. This latter mechanism must be consid-
ered since the initial step of the alkaline hydrolysis
reaction of nonphenolic â-O-4 lignin models normally
involves such a process.3
The rearrangement product 4 results from a migration
of the B ring from the â-oxygen to the R-oxygen of the
side chain, or in lignin terminology it is a â-O-4 to R-O-4
rearrangement. The identity of 4 was determined to be
a,8
2
-(4-formyl-2-methoxyphenoxy)-2-(3,4-dimethoxyphenyl)-
1
13
ethanol using H, C, CHCOR, COSY2Q, and INAPT
The benzylic hydroxyl oxygen of 1 was labeled with
1
17,18
NMR techniques. In the H NMR, the R-H in 1 absorbs
O, to provide mechanistic evidence on whether the
at 5.09 (m, 1H) ppm and the â-H at 4.17 (d, 2H) ppm,
whereas in 4 the R-H was observed at 4.23 (m, 1H) and
the â-H at 3.8 ppm. The â-H is underneath the three
OMe H’s but is clearly seen in the CHCOR spectrum. The
chemical shifts of the R- and â-carbons in 1 and 4 have
even more pronounced differences. The R-C absorbs at
rearrangement went through intermediate 2 or 3, shown
in Scheme 1. If the pathway proceeds through the spiro-
4c
Meisenheimer intermediate 2, then 4a would be ob-
tained. Alternatively, if the neighboring-group epoxide
pathway is followed, the rearrangement product of 1
would be 4b with the labeled oxygen on the â-hydroxyl
group.
7
2.4 ppm in 1 and at 83.1 ppm in 4, a nearly 11 ppm
downfield shift. The â-C shifts in the other direction
from 75.5 ppm on 1 to 67.5 ppm on 4) because the B
The 17O NMR of 1 labeled on the benzylic hydroxyl
(
9
gave a peak at 20.6 ppm, which is in the hydroxyl region,
aryl ring has moved from the â- to the R-carbon. MS
analysis of 4 gave major ions (m/e) of 151/152 and 180.
These masses are assigned to the two ions formed from
1
7
while the O NMR of 4 had a peak at 90.6 ppm,
indicating the presence of an 17O aryl ether (structure
9
4
a not 4b). The MS of labeled 1 showed a small parent
*
peak at m/e 332 and another small peak at m/e 334
Corresponding author: phone, (601) 325-7612; fax, (601) 325-1618;
e-mail, thf1@ra.msstate.edu.
†
J ournal Article No. FPA-088-0397 of the Forest and Wildlife
Research Center, Mississippi State University
(4) (a) Parker, K. A.; Coburn, C. A. J . Org. Chem. 1992, 57, 97. (b)
Bernasxoni, C. F.; Wang, H. J . Am. Chem. Soc. 1976, 98, 6265. (c)
Strass, M. J . Acc. of Chem. Res 1974, 7, 181.
(5) (a) Makosza, M. Synthesis 1991, 103. (b) Esser, F.; Pook, K.
Synthesis 1992, 596. (c) Ahmed, Z.; Cava, M. P. Tetrahedron Lett. 1984,
803.
(1) LigninssOccurrence, Formation, Structure and Reactions; Sar-
kanen, K. V., Ludwig, C. H., Eds.; Wiley Interscience: New York, 1971;
p 205.
(
2) (a) Fisher, T. H.; Dershem, S. M.; Schultz, T. P. J . Org. Chem.
988, 53, 1504. (b) Schultz, T. P.; Fisher, T. H. Tappi J . 1989, 72, 223.
c) Schultz, T. P.; Hubbard, T. H.; Fisher, T. H. Holzforschung 1995,
1
(
(6) Panetta, C. A.; Fang, Z.; Heimer, N. E. J . Org. Chem. 1993, 58,
6146.
4
9, 528.
(
3) (a) Hubbard, T. F.; Schultz, T. P.; Fisher, T. H. Holzforschung
(7) Lindeberg, O.; Walding, J . Tappi J . 1987, 70, 119.
(8) Gierer, J .; Nor e´ n, I. Acta Chem. Scand. 1962, 16, 1976.
1
992, 46, 315. (b) Collier, W. E.; Fisher, T. H.; Ingram, L. L.; Harris,
1
7
A. L.; Schultz, T. P. Holzforschung 1996, 50, 420. (c) Criss, D. L.;
Collier, W. E.; Fisher, T. H.; Schultz, T. P. Holzforschung, submitted
for publication.
(9) Chandrasekaran, S. In
O NMR Spectroscopy in Organic
Chemistry; Boykin, D. W., Ed.; CRC Press: Boca Raton, FL, 1990; pp
152, 189.
S0022-3263(97)00936-5 CCC: $14.00 © 1997 American Chemical Society

7
886 J . Org. Chem., Vol. 62, No. 22, 1997
Notes
Sch em e 1. Tw o P ossible Mech a n ism s for Rea r r a n gem en t of 1 to 4: Sp ir o-Meisen h eim er Com p lex
a
2
or Ep oxid e 3
a
An asterisk (*) ) 17/18O label.
the procedure of Collier et al.3b 1H NMR (acetone-d
3.79, 3.81, 3.91, 4.17 (d, 2H, J ) 5.8 Hz, H-â), 4.73 (d, 1H, J )
3.9 Hz, R-OH), 5.09 (m, 1H, H-R), 6.93 (d, 1H, J ) 8.2 Hz), 7.03
): δ, ppm:
(
P + 2) of essentially equal intensity, indicating that 1
6
1
8
was labeled with approximately 50% O. Dehydration
of 1 gave an ion at m/e of 314 (M - H O) of 51%
2
•
+
(
dd, 1H, J ) 2.0, 8.2 Hz), 7.18 (d, 1H, J ) 2.0 Hz), 7.18 (d, 1H,
intensity with only a small (less than 2%) m/e 316 peak,
further indicating that the label was on the hydroxyl
group. The m/e 180 peak was accompanied by a signifi-
cant 18O (P + 2) peak, while the m/e 151/152 peaks had
only small peaks at m/e 153/154. This result was
expected since the label was on the 3,4-dimethoxyphenyl
side chain. MS/direct probe of labeled 4 gave a m/e 180
peak, but no m/e 182 (P + 2) peak, and large peak
intensities at m/e 153/154 along with the normally
observed m/e 151/152 peaks. Consequently, on the basis
J ) 8.2 Hz), 7.43 (d, 1H, J ) 1.9 Hz), 7.50 (dd, 1H, J ) 1.9, 82
13
Hz). C NMR (acetone-d ): δ 56.1, 56.2, 56.3, 72.4 (C-R), 75.5
6
(C-â), 110.9, 111.5, 112.6, 113.5, 119.4, 126.7, 131.4, 135.3, 149.9,
o
3a
150.3, 151.0, 155.0, 191.2. Mp: 112-114 C (lit. mp 113-114
o
C).
[
1
7 /1 8
O H ]-2-(4 -F o r m y l -2-m e t h o x y p h e n o x y )-1 -(3,4 -
d im eth oxyp h en yl)eth a n ol (1). Synthesis of labeled 1 started
with the dioxolane derivative 7 [2-(4-(1,3-dioxolan-2-yl)phenoxy)-
3a
1
-(3,4-dimethoxyphenyl)-1-ethanone]) under basic conditions
to prevent colabeling the 4′-formyl. The protected ketone 7
(0.601 mmol), KOH (1.2 mmol), 1 mL of 10% O water
(containing about 70% 18O), and 10 mL of dioxane were stirred
at rt. After 4 h NaBH (3.01 mmol) was added, and the mixture
4
was stirred overnight. Then 10 mL of acetone was introduced,
the mixture stirred for 30 min, and 100 mL of water with 5 drops
1
7
of both the 1 O NMR and O MS data, we conclude that
the rearrangement product of labeled 1 is 4a . Thus, the
results are consistent with the proposed mechanism
involving intermediate 2.
7
18
2 2
HCl added. The mixture was extracted three times with CH Cl .
The crude product was recrystallized from EtOH giving white
o
crystals, mp 112-114 C, 49% yield. Precise isotope enrichment
Exp er im en ta l Section
1
7
18
could not be determined due to the presence of both O and
O
Gen er a l Meth od s. Melting points were determined on a
Mel-Temp apparatus and are uncorrected. Elemental analyses
were performed by Galbraith Labs of Knoxville, TN. Water (10%
and the large P-1 peak typical of benzaldehydes but was
estimated as approximately 50% 18O and 7% O. H and
17 1 13
C
1
7
NMR spectra were identical to those of nonlabeled 1. O NMR
(CDCl ): δ 20.1 (br s).
1
8
17
18
O) was obtained from Aldrich, and water (10% O, 70% O)
3
1
was obtained from Cambridge Isotope Labs. H NMR spectra
2-(4-F o r m y l-2-m e t h o x y p h e n o x y )-2-(3,4-d im e t h o x y -
p h en yl)eth a n ol (4). Compound 1, 0.101 g, was dissolved in
2.5 mL of dioxane, and 5.5 mL of 0.5 N NaOH was added, with
overnight stirring at rt. The mixture was extracted three times
1
3
17
were run at 300 MHz, C NMR at 75.6 MHz, and O NMR at
4
1
7
0.8 MHz. The O NMR spectra were collected into 16K data
sets over a spectral width of 38.5 kHz using a 60° pulse, 15 000
scans, and 250 Hz line broadening. Mass spectra were obtained
with either GC or direct probe sample introduction and EIMS
at 70 eV. HPLC analysis used a 10 µm Econsil C-18 reverse-
phase column with UV detector at 280 nm and a gradient elution
using acetonitrile and water (1% acetic acid) starting with 25%
acetonitrile for 5 min, then ramped to 95% acetonitrile over 10
min, and held for 5 min. The rearranged product 4 eluted
slightly faster than 1.
2 2
with CH Cl , washed with water, and dried. The mixture of
isomers 1 and 4 was separated using open column silica gel
chromatography. The column was slurry-packed with Waltman
60 A, 70-230 mesh, silica gel with the elution monitored by UV
at 280 nm. The elution solvent was a 40:60 mixture of ethyl
acetate:cyclohexane which was gradually increased to 70% ethyl
acetate. The starting compound 1 eluted first. The eluted
compound 4 had a single peak on HPLC. Attempts to recrystal-
lize 4 were unsuccessful, and it was observed that 4 by itself or
in solution slowly turned dark. MS direct probe (% intensity):
2
-(4-F o r m y l-2-m e t h o x y p h e n o x y )-1-(3,4-d im e t h o x y -
p h en yl)eth a n ol (1). Ethanol 1 was synthesized according to

Notes
80 (25) [probably 1-(3,4-dimethoxyphenyl)ethan-2-one] , 152
J . Org. Chem., Vol. 62, No. 22, 1997 7887
191.2. 17O NMR (CDCl
H O :
20 6
•
+
1
3
): δ 90.6 (br s). Anal. Calcd for C18
C, 65.05; H, 6.08. Found: C, 64.41; H, 6.34.
•
+
•+
•+
(
10), vanillin , 151 (100) [vanillin - 1], 107 (10) [anisole
-
1
4
6
1
1
]. 1H NMR (acetone-d
6
): δ 3.76, 3.79, 3.95, 3.8 (d, 2H, H-â),
.23 (m, 1H, R-OH), 5.46 (dd, 1H, H-R), 6.89 (d, 1H, J ) 8.2 Hz),
.97 (dd, 1H, J ) 2.0, 8.2 Hz), 7.08 (d, 1H, J ) 8.2 Hz), 7.10 (d,
H, J ) 2.0 Hz), 7.36 (dd, 1H, J ) 1.9, 8.2 Hz) 7.41 (d, 1H, J )
Ack n ow led gm en t. This research was funded by
USDA/WUR Grant 96-34158-2557, NSF Grant EPS-
1
3
.9 Hz).
6 3
C NMR (acetone-d ): δ 29.80 (CD of solvent is
9
452857, and the State of Mississippi.
reference) 55.96, 55.99, 56.2, 67.5 (C-â), 83.1 (C-R), 110.8, 111.2,
1
12.5, 115.4, 119.7, 126.2, 131.3, 131.5, 150.1, 150.4, 151.3, 154.1,
J O970936Z